CN116813542A - Pharmaceutical polycrystals of milrinone - Google Patents

Pharmaceutical polycrystals of milrinone Download PDF

Info

Publication number
CN116813542A
CN116813542A CN202210280420.4A CN202210280420A CN116813542A CN 116813542 A CN116813542 A CN 116813542A CN 202210280420 A CN202210280420 A CN 202210280420A CN 116813542 A CN116813542 A CN 116813542A
Authority
CN
China
Prior art keywords
milrinone
acid
crystal
degrees
crystals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210280420.4A
Other languages
Chinese (zh)
Inventor
翟立海
夏祥来
李玲
郑家芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong New Time Pharmaceutical Co Ltd
Original Assignee
Shandong New Time Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong New Time Pharmaceutical Co Ltd filed Critical Shandong New Time Pharmaceutical Co Ltd
Priority to CN202210280420.4A priority Critical patent/CN116813542A/en
Publication of CN116813542A publication Critical patent/CN116813542A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and provides a milriness pesticide polycrystal which has the advantages of simple preparation method, easy control of crystallization process and good reproducibility. The prepared milrinone-malonic acid crystal, milrinone-fumaric acid crystal, milrinone-maleic acid crystal, milrinone-oxalic acid crystal, milrinone-4-hydroxy cinnamic acid crystal and milrinone-1-hydroxy-2-naphthoic acid crystal have obviously enhanced stability compared with the free alkali and the crystal forms thereof, thereby being beneficial to the storage, transportation and application of products in preparation of preparations; the dissolubility is obviously improved, and the bioavailability and the absorption performance of milrinone can be improved.

Description

Pharmaceutical polycrystals of milrinone
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a milrinone pharmaceutical polycrystal, a preparation method and application thereof.
Background
Milrinone (milrinone) with chemical name 1, 6-dihydro-2-methyl-6-oxo- [3, 4-bipyridine]-5-carbonitrile of formula C 12 H 9 N 3 O, molecular weight 211.22, is white or white-like crystalline powder, and has the structural formula:
milrinone was first developed by Sterling corporation in the united states to successfully produce an anti-heart failure drug, which was first approved by the FDA in the united states in 1987, formally marketed in the united states in 1992, and subsequently marketed in the united kingdom, france, germany, the netherlands, belgium, etc.
Milrinone is a phosphodiesterase inhibitor, is a derivative of amirinone, and has the same action mechanism as amirinone. It is effective for oral administration and intravenous injection, and has positive muscle strength and vasodilatation effects. Is suitable for short-term treatment of patients with severe congestive heart failure, the curative effect of which is 10-30 times stronger than that of amrinone, the tolerance is better, and the adverse reaction is less. The positive inotropic effect is mainly to increase the concentration of Cyclic Adenosine Monophosphate (CAMP) in myocardial cells by inhibiting phosphodiesterase, increase intracellular calcium, strengthen myocardial contractility and increase cardiac output. It is considered to be a high-efficiency, low-toxicity, non-digitalis and non-sympathomimetic cardiotonic, and has remarkable effects on severe heart failure and pulmonary edema caused by ischemic heart disease, dilated cardiomyopathy, etc., and is superior to dopamine, less in adverse reaction and not increasing heart rate. Therefore, the medicine plays an increasingly important role in treating Congestive Heart Failure (CHF), peripheral vascular dilation and the like.
Researches show that milrinone has poor water solubility, is almost insoluble in water, has poor in vivo dissolution and absorption effects, and has adverse reaction when orally taken; the existing milrinone injection has the problems of poor stability and easy degradation. Although the prior art discloses some methods of attempting to improve the solubility or stability of milrinone, none of them achieve the desired effect, nor do they improve the disadvantages of poor absorption. For example, patent CN1951919a discloses that the inorganic acid salts of milrinone series are used for preparing freeze-dried formulations for injection, and although the solubility of milrinone can be improved, stability problems still exist generally; for example, patent CN102558044a discloses a crystallization method of milrinone, and the milrinone obtained by the method has high purity and good crystal form, but the physicochemical properties of milrinone are not improved yet; in addition, patent CN106361710a describes that, in order to solve the problems of poor stability of milrinone lactate, easy degradation and obvious increase of related substances in the prior art, the stability of injection is increased by adding a certain amount of vitamin E and glutathione in the prescription and using a new crystal form, and the degradation reaction is reduced, but the problem of poor solubility of milrinone is not overcome by using a new crystal form. Therefore, the preparation method provides the milrinone medicinal crystal with good solubility, high stability and good application prospect, provides a solution for developing the preparation with the effect of improving in vivo absorption, and is still a problem to be solved in the field.
Disclosure of Invention
The present invention has found through research that milrinone and carboxylic acid group containing compounds can form stable crystals and that these crystals may exhibit advantageous physicochemical properties in one or more aspects, such as improved solubility, better stability, etc.
The specific technical content of the invention is as follows:
the invention provides a milrinone drug polycrystal, wherein the crystal structure of the drug polycrystal contains milrinone and a compound containing carboxylic acid groups; specifically, the carboxylic acid-containing compound is selected from malonic acid, fumaric acid, maleic acid, oxalic acid, 4-hydroxycinnamic acid, 1-hydroxy-2-naphthoic acid or 2-indolecarboxylic acid.
Preferably, the milrinone polycrystal is: milrinone-malonic acid crystal, milrinone-fumaric acid crystal, milrinone-maleic acid crystal, milrinone-oxalic acid crystal, milrinone-4-hydroxy cinnamic acid crystal, milrinone-1-hydroxy-2-naphthoic acid crystal, and milrinone-2-indolecarboxylic acid crystal.
The milrinone-malonic acid crystal disclosed by the invention uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 10.3+/-0.2 DEG, 15.3+/-0.2 DEG and 24.3+/-0.2 deg.
Preferably, the milrinone-malonic acid crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray diffraction pattern shown in figure 1.
Preferably, the milrinone-malonic acid crystal has a molecular formula of C 15 H 13 N 3 O 5 The crystallographic parameters were: triclinic crystal system, space group is P-1, unit cell parameters are:α= 89.036 (6) °, β= 84.721 (6) °, γ= 82.091 (6) °, unit cell volume +.>
The milrinone-fumaric acid crystal adopts Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 15.6+/-0.2 degrees, 18.3+/-0.2 degrees, 23.7+/-0.2 degrees, 26.1+/-0.2 degrees, 26.2+/-0.2 degrees and 29.6+/-0.2 degrees.
Preferably, the milrinone-fumaric acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 10.4+/-0.2 degrees, 15.6+/-0.2 degrees, 18.3+/-0.2 degrees, 20.6+/-0.2 degrees, 23.7+/-0.2 degrees, 25.4+/-0.2 degrees, 25.7+/-0.2 degrees, 26.1+/-0.2 degrees, 26.2+/-0.2 degrees, 26.9+/-0.2 degrees and 29.6+/-0.2 degrees and 31.2+/-0.2 degrees.
Preferably, the milrinone-fumaric acid crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray diffraction spectrum shown in figure 4.
Preferably, the milrinone-fumaric acid crystal has a molecular formula of C 28 H 22 N 6 O 6 The crystallographic parameters were: triclinic crystal system, space group is P-1, unit cell parameters are:α= 70.6750 (10) °, β= 72.4550 (10) °, γ= 84.4810 (10) °, unit cell volume +.>
The milrinone-maleic acid crystal adopts Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 17.1+/-0.2 degrees, 19.0+/-0.2 degrees, 20.0+/-0.2 degrees, 22.6+/-0.2 degrees, 23.2+/-0.2 degrees, 25.2+/-0.2 degrees and 27.8+/-0.2 degrees.
Preferably, the milrinone-maleic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 6.2+/-0.2 degrees, 11.6+/-0.2 degrees, 14.9+/-0.2 degrees, 17.1+/-0.2 degrees, 19.0+/-0.2 degrees, 20.0+/-0.2 degrees, 22.6+/-0.2 degrees, 23.2+/-0.2 degrees, 25.2+/-0.2 degrees, 25.4+/-0.2 degrees, 26.3+/-0.2 degrees, 27.8+/-0.2 degrees, 28.5+/-0.2 degrees and 30.0+/-0.2 degrees.
Preferably, the milrinone-maleic acid crystals use Cu-kα radiation, the characteristic peaks of which correspond to the X-ray diffraction pattern shown in fig. 7.
Preferably, the milrinone-maleic acid crystal has a molecular formula of C 16 H 13 N 3 O 5 The crystallographic parameters were: monoclinic crystal system with space group P2 1 And/c, the unit cell parameters are as follows:α=90 °, β= 99.0870 (10) °, γ=90°, unit cell volume +.>
The milrinone-oxalic acid crystal adopts Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 14.5+/-0.2 degrees, 18.5+/-0.2 degrees, 23.2+/-0.2 degrees, 28.8+/-0.2 degrees and 36.8+/-0.2 degrees.
Preferably, the milrinone-oxalic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 12.9+/-0.2 degrees, 14.5+/-0.2 degrees, 18.5+/-0.2 degrees, 23.2+/-0.2 degrees, 28.8+/-0.2 degrees, 30.9+/-0.2 degrees, 34.8+/-0.2 degrees, 36.8+/-0.2 degrees, 37.3+/-0.2 degrees, 39.3+/-0.2 degrees and 39.7+/-0.2 degrees.
Preferably, the milrinone-oxalic acid crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray diffraction spectrum shown in figure 10.
Preferably, the milrinone-oxalic acid crystal has a molecular formula of C 14 H 11 N 3 O 5 The crystallographic parameters were: monoclinic crystal system with space group P2 1 And/n, the unit cell parameters are:α=90 °, β= 90.7445 (12) °, γ=90°, unit cell volume +.>
The milrinone-4-hydroxy cinnamic acid crystal adopts Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 5.9+/-0.2 degrees, 14.7+/-0.2 degrees, 19.0+/-0.2 degrees, 25.0+/-0.2 degrees, 25.2+/-0.2 degrees and 30.8+/-0.2 degrees.
Preferably, the milrinone-4-hydroxy cinnamic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 5.9+/-0.2 degrees, 7.4+/-0.2 degrees, 14.7+/-0.2 degrees, 19.0+/-0.2 degrees, 22.9+/-0.2 degrees, 27.9+/-0.2 degrees, 29.5+/-0.2 degrees, 30.8+/-0.2 degrees, 31.6+/-0.2 degrees and 34.2+/-0.2 degrees.
Preferably, the milrinone-4-hydroxy cinnamic acid crystal uses Cu-K alpha radiation, and its characteristic peak is in accordance with the X-ray diffraction pattern shown in figure 13.
Preferably, the milrinone-4-hydroxy cinnamic acid crystal has a molecular formula of C 21 H 17 N 3 O 4 The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of:α= 93.9650 (10) °, β= 94.6000 (10) °, γ= 109.6110 (10) °, unit cell volume +.>
The milrinone-1-hydroxy-2-naphthoic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 12.9+/-0.2 degrees, 15.5+/-0.2 degrees, 24.4+/-0.2 degrees, 25.0+/-0.2 degrees and 25.1+/-0.2 degrees.
Preferably, the milrinone-1-hydroxy-2-naphthoic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 7.1+/-0.2 degrees, 12.2+/-0.2 degrees, 12.9+/-0.2 degrees, 15.5+/-0.2 degrees, 16.7+/-0.2 degrees, 24.4+/-0.2 degrees, 25.0+/-0.2 degrees, 25.1+/-0.2 degrees, 27.3+/-0.2 degrees and 31.9+/-0.2 degrees.
Preferably, the milrinone-1-hydroxy-2-naphthoic acid crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray diffraction spectrum shown in figure 16.
Preferably, the milrinone-1-hydroxy-2-naphthoic acid crystal is divided into two partsThe sub-formula is C 23 H 17 N 3 O 4 The crystallographic parameters were: triclinic crystal system, space group is P-1, unit cell parameters are:α= 70.444 (10) °, β= 86.165 (9) °, γ= 72.457 (9) °, unit cell volume +.>
The milrinone-2-indolecarboxylic acid crystal adopts Cu-K alpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at least at 7.9+/-0.2 degrees, 12.5+/-0.2 degrees, 16.7+/-0.2 degrees, 19.2+/-0.2 degrees, 22.9+/-0.2 degrees, 25.4+/-0.2 degrees and 26.5+/-0.2 degrees.
Preferably, the milrinone-2-indolecarboxylic acid crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 7.9+/-0.2 degrees, 11.2+/-0.2 degrees, 12.5+/-0.2 degrees, 15.5+/-0.2 degrees, 16.7+/-0.2 degrees, 19.2+/-0.2 degrees, 20.2+/-0.2 degrees, 21.1+/-0.2 degrees, 22.2+/-0.2 degrees, 22.9+/-0.2 degrees, 25.4+/-0.2 degrees, 25.8+/-0.2 degrees, 26.5+/-0.2 degrees, 26.6+/-0.2 degrees and 28.2+/-0.2 degrees.
Preferably, the milrinone-2-indolecarboxylic acid crystal uses Cu-K alpha radiation, and the characteristic peak thereof accords with an X-ray diffraction pattern shown in figure 19.
Preferably, the milrinone-2-indolecarboxylic acid crystal has a molecular formula of C 21 H 16 N 4 O 3 The crystallographic parameters were: monoclinic crystal system with space group P2 1 And/c, the unit cell parameters are as follows: α=90 °, β= 98.093 (2) °, γ=90°, unit cell volume +.>
In another aspect, the present invention provides a method for preparing the pharmaceutical polymorph, comprising the steps of:
dissolving milrinone and a compound containing carboxylic acid in a mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain medicine crystals.
Preferably, the mixed solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetonitrile, acetone, and trifluoroethanol.
Preferably, the molar ratio of milrinone to carboxylic acid-containing compound is 1:0.2 to 2.
Preferably, the carboxylic acid-containing compound is malonic acid, fumaric acid, maleic acid, oxalic acid, 4-hydroxycinnamic acid, 1-hydroxy-2-naphthoic acid or 2-indolecarboxylic acid.
Preferably, the heating temperature is 40-70 ℃.
Preferably, the temperature of the cooling crystallization is 0-30 ℃.
Preferably, the crystallization time is 1 to 72 hours.
Preferably, the drying temperature is 40-70 ℃ and the drying time is 1-24 hours.
Further preferably, the present invention provides a method for preparing milrinone-malonic acid crystals, comprising the steps of:
and (3) dissolving milrinone and malonic acid in the mixed solvent, heating and stirring, filtering, cooling, standing, crystallizing, filtering and drying to obtain milrinone-malonic acid crystals.
Preferably, the solvent is selected from the group consisting of a mixed solvent of methanol and ethanol, acetonitrile, water, acetone or trifluoroethanol; particularly preferred are mixed solvents of methanol and trifluoroethanol or acetone.
Preferably, the mass-volume ratio of the milrinone to the mixed solvent is 21.1:1-3; preferably 21.1:1.5 to 2.5, mass in mg and volume in mL.
Preferably, the molar ratio of milrinone to malonic acid is 1:0.8 to 1.1.
Preferably, the heating temperature is 50-70 ℃.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; the temperature of the cooling crystallization is preferably 10-15 ℃.
Preferably, the crystallization time is 8-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a method for preparing milrinone-fumaric acid crystals, comprising the steps of:
and dissolving milrinone and fumaric acid in the mixed solvent, heating, stirring, filtering, cooling, standing, crystallizing, filtering and drying to obtain milrinone-fumaric acid crystals.
Preferably, the solvent is selected from the group consisting of a mixed solvent of methanol and ethanol, acetonitrile, water, acetone or trifluoroethanol; particularly preferred are mixed solvents of methanol and trifluoroethanol or acetone.
Preferably, the mass-volume ratio of the milrinone to the mixed solvent is 21.1:1-3; preferably 21.1:1.5 to 2.5, mass in mg and volume in mL.
Preferably, the molar ratio of milrinone to fumaric acid is 2:0.8 to 1.5.
Preferably, the heating temperature is 50-70 ℃; further preferably 60 ℃.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; the temperature of the cooling crystallization is preferably 10-15 ℃.
Preferably, the crystallization time is 8-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a method for preparing milrinone-maleic acid crystals, comprising the steps of:
dissolving milrinone and maleic acid in a mixed solvent, heating, stirring, filtering, cooling, standing, crystallizing, filtering and drying to obtain milrinone-maleic acid crystals.
Preferably, the solvent is selected from the group consisting of a mixed solvent of methanol and ethanol, acetonitrile, water, acetone or trifluoroethanol; particularly preferred are mixed solvents of methanol and trifluoroethanol or acetone.
Preferably, the mass volume ratio of the milrinone to the mixed solvent is 21.1:1-3; preferably 21.1:1.5 to 2.5, mass in mg and volume in mL.
Preferably, the molar ratio of milrinone to maleic acid is 1:0.8 to 1.1.
Preferably, the heating temperature is 50-70 ℃.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; the temperature of the cooling crystallization is preferably 10-15 ℃.
Preferably, the crystallization time is 8-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a method for preparing milrinone-oxalic acid crystals, comprising the steps of:
and dissolving milrinone and oxalic acid in the mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain milrinone-oxalic acid crystals.
Preferably, the solvent is selected from the group consisting of a mixed solvent of methanol and ethanol, acetonitrile, water, acetone or trifluoroethanol; particularly preferred are mixed solvents of methanol and trifluoroethanol or acetone.
Preferably, the mass-volume ratio of the milrinone to the mixed solvent is 21.1:1-3; preferably 21.1:1.5 to 2.5, mass in mg and volume in mL.
Preferably, the molar ratio of milrinone to oxalic acid is 1:0.8 to 1.1.
Preferably, the heating temperature is 50-70 ℃; preferably 60 ℃.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; the temperature of the cooling crystallization is preferably 10-15 ℃.
Preferably, the crystallization time is 8-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a method for preparing milrinone-4-hydroxycinnamic acid crystals, comprising the steps of:
dissolving milrinone and 4-hydroxy cinnamic acid in a mixed solvent, heating, stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain milrinone-4-hydroxy cinnamic acid crystal.
Preferably, the mixed solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone and trifluoroethanol; particularly preferred are combinations of two or more of ethanol, methanol, trifluoroethanol.
Preferably, the mass-volume ratio of the milrinone to the mixed solvent is 21.1:2-5; preferably 21.1:3-4, mass in mg and volume in mL.
Preferably, the molar ratio of milrinone to 4-hydroxy cinnamic acid is 1:0.5 to 1.2.
Preferably, the heating temperature is 40-60 ℃.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; the temperature of the cooling crystallization is preferably 20-25 ℃.
Preferably, the crystallization time is 16-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a process for preparing milrinone-1-hydroxy-2-naphthoic acid crystals comprising the steps of:
dissolving milrinone and 1-hydroxy-2-naphthoic acid in a mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain milrinone-1-hydroxy-2-naphthoic acid crystals.
Preferably, the solvent is selected from the group consisting of a mixed solvent of methanol and ethanol, acetonitrile, water, acetone or trifluoroethanol; particularly preferred are mixed solvents of methanol and trifluoroethanol or acetone.
Preferably, the mass-volume ratio of the milrinone to the mixed solvent is 21.1:1-3; preferably 21.1:1.5 to 2.5, mass in mg and volume in mL.
Preferably, the molar ratio of milrinone to 1-hydroxy-2-naphthoic acid is 1:0.8 to 1.1; preferably 1:1.
preferably, the heating temperature is 50-70 ℃; preferably 60 ℃.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; the temperature of the cooling crystallization is preferably 10-15 ℃.
Preferably, the crystallization time is 8-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
Further preferably, the present invention provides a method for preparing milrinone-2-indolecarboxylic acid crystals, comprising the steps of:
dissolving milrinone and 2-indolecarboxylic acid in a mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain milrinone-2-indolecarboxylic acid crystals.
Preferably, the solvent is selected from the group consisting of a mixed solvent of ethanol and methanol, isopropanol, acetonitrile, acetone or trifluoroethanol; particularly preferred are mixed solvents of ethanol and trifluoroethanol and/or acetone.
Preferably, the mass-volume ratio of the milrinone to the mixed solvent is 21.1:1-5, the mass is in mg and the volume is in mL.
Preferably, the molar ratio of milrinone to 2-indolecarboxylic acid is 1:0.8 to 1.1.
Preferably, the heating temperature is 50-70 ℃.
Preferably, the temperature reduction crystallization temperature is 10-20 ℃; the temperature of the cooling crystallization is preferably 13-17 ℃.
Preferably, the crystallization time is 24-72 hours.
Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
In yet another aspect, there is provided use of the milrinone polymorph of the invention in the manufacture of a medicament for the treatment of a disease, including cardiovascular and cerebrovascular diseases; heart failure is preferred.
Compared with the prior art, the invention has the technical effects that:
the preparation method of the milrinone pesticide polycrystal provided by the invention is simple to operate, the crystallization process is easy to control, and the reproducibility is good. The milrinone-malonic acid crystal, the milrinone-fumaric acid crystal, the milrinone-maleic acid crystal, the milrinone-oxalic acid crystal, the milrinone-4-hydroxy cinnamic acid crystal and the milrinone-1-hydroxy-2-naphthoic acid crystal have significantly enhanced stability compared with the free alkali and the crystal forms thereof, thereby being beneficial to the storage and transportation of products and the application in preparation of preparations; has obviously improved solubility, and is helpful for improving the bioavailability and absorption performance of milrinone. The milrinone polycrystal with good physicochemical properties provides more drug choices for treating diseases, and has great clinical research and development values.
Drawings
FIG. 1 PXRD spectra of milrinone-malonic acid crystals.
FIG. 2 ORTEP diagram of milrinone-malonic acid crystals.
FIG. 3 shows a hydrogen bonding diagram of milrinone-malonic acid crystals.
Fig. 4 PXRD pattern of milrinone-fumaric acid crystals.
FIG. 5 ORTEP diagram of milrinone-fumaric acid crystals.
FIG. 6 shows hydrogen bonding diagrams of milrinone-fumaric acid crystals.
Fig. 7 PXRD pattern of milrinone-maleic acid crystals.
FIG. 8 ORTEP diagram of milrinone-maleic acid crystals.
FIG. 9 shows hydrogen bonding diagrams of milrinone-maleic acid crystals.
FIG. 10 PXRD spectra of milrinone-oxalic acid crystals.
FIG. 11 ORTEP diagram of milrinone-oxalic acid crystals.
FIG. 12 hydrogen bonding diagram of milrinone-oxalic acid crystals.
FIG. 13 PXRD spectra of milrinone-4-hydroxycinnamic acid crystals.
FIG. 14 ORTEP diagram of milrinone-4-hydroxycinnamic acid crystals.
FIG. 15 shows a hydrogen bonding diagram of milrinone-4-hydroxycinnamic acid crystals.
FIG. 16 PXRD spectra of milrinone-1-hydroxy-2-naphthoic acid crystals.
FIG. 17 ORTEP diagram of milrinone-1-hydroxy-2-naphthoic acid crystal.
FIG. 18 shows a hydrogen bonding diagram of milrinone-1-hydroxy-2-naphthoic acid crystals.
FIG. 19 PXRD spectra of milrinone-2-indolecarboxylic acid crystals.
FIG. 20 ORTEP diagram of milrinone-2-indolecarboxylic acid crystals.
FIG. 21 shows a hydrogen bonding diagram of milrinone-2-indolecarboxylic acid crystals.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1 milrinone-malonic acid crystals
Preparation example 1
Milrinone (211.1 mg) and malonic acid (104.1 mg) are dissolved in a mixed solvent of methanol (10 mL) and trifluoroethanol (10 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, stood at 15 ℃ for volatilization and crystallization for 24 hours, filtered and dried at 60 ℃ for 12 hours to obtain milrinone-malonic acid crystals, and the yield is: 95.2%, purity: 99.91%.
Preparation example 2
Milrinone (211.1 mg) and malonic acid (109.3 mg) are dissolved in a mixed solvent of methanol (10 mL) and acetone (10 mL), the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at 10 ℃ for volatilization and crystallization for 24 hours, the filtered mixture is dried at 60 ℃ for 12 hours to obtain milrinone-malonic acid crystals, and the yield is: 95.8%, purity: 99.92%.
Preparation example 3
Milrinone (126.7 mg) and malonic acid (81.2 mg) are dissolved in a mixed solvent of methanol (15 mL) and acetonitrile (15 mL), heated and stirred in a water bath at 55 ℃ until the components are completely dissolved, filtered, and subjected to standing, volatilizing and crystallization at 20 ℃ for 48 hours, filtered and dried at 60 ℃ for 12 hours to obtain milrinone-malonic acid crystals, and the yield is: 89.3%, purity: 99.90%.
Preparation example 4
Milrinone (105.6 mg) and malonic acid (52.1 mg) are dissolved in a mixed solvent of methanol (10 mL) and trifluoroethanol (10 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, stood at 30 ℃ for volatilization and crystallization for 72h, filtered and dried at 60 ℃ for 12h to obtain milrinone-malonic acid crystals, and the yield is: 87.1%, purity: 99.91%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallographic data (as in table 1) for testing and resolving the crystalline form of milrinone-malonic acid prepared according to the invention are: triclinic crystal system, space group is P-1, unit cell parameters are:α= 89.036 (6) °, β= 84.721 (6) °, γ= 82.091 (6) °, unit cell volume +.>
TABLE 1 Milrinon-malonic acid Crystal principal crystallographic data
The ORTEP diagram of the milrinone-malonic acid crystals of the invention shows that one molecule of milrinone binds one molecule of malonic acid in this crystalline form, as shown in fig. 2. The hydrogen bond diagram of milrinone-malonic acid of the invention is shown in figure 3. According to the crystallographic data, the characteristic peaks in the corresponding X-ray diffraction pattern (Cu-K alpha) are shown in the accompanying figures 1 and 2.
TABLE 2 PXRD peaks for milrinone-malonic acid crystals
Example 2 milrinone-fumaric acid crystals
Preparation example 1
Milrinone (422 mg) and fumaric acid (116 mg) are dissolved in a mixed solvent of methanol (20 mL) and trifluoroethanol (20 mL), the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood and volatilized at 15 ℃ for crystallization for 48 hours, the mixture is filtered, and the mixture is dried at 65 ℃ for 8 hours to obtain milrinone-fumaric acid crystals, so that the yield: 94.3%, purity: 99.91%.
Preparation example 2
Milrinone (422 mg) and fumaric acid (128 mg) are dissolved in a mixed solvent of methanol (20 mL) and acetone (20 mL), the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at 15 ℃ for volatilization and crystallization for 24 hours, the mixture is filtered, and the mixture is dried at 65 ℃ for 8 hours to obtain milrinone-fumaric acid crystals, so that the yield is: 93.8%, purity: 99.92%.
Preparation example 3
Milrinone (211 mg) and fumaric acid (60 mg) are dissolved in a mixed solvent of methanol (25 mL) and ethanol (25 mL), the mixture is heated and stirred in a water bath at 70 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at 30 ℃ for volatilization and crystallization for 72h, the mixture is filtered, and the mixture is dried at 65 ℃ for 12h to obtain milrinone-fumaric acid crystals, and the yield is: 90.2% of purity: 99.91%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallographic data (as in table 3) for testing and resolving the crystalline form of milrinone-fumaric acid prepared according to the invention are: triclinic crystal system, space group is P-1, unit cell parameters are:α= 70.6750 (10) °, β= 72.4550 (10) °, γ= 84.4810 (10) °, unit cell volume +.>
TABLE 3 Milrinon-fumaric acid Crystal principal crystallographic data
The ORTEP diagram of the milrinone-fumaric acid crystals of the present invention shows that two molecules of milrinone bind to one molecule of fumaric acid in the crystalline form, as shown in fig. 5. The hydrogen bond diagram of milrinone-fumaric acid of the invention is shown in figure 6. According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray diffraction pattern (Cu-K alpha) are shown in FIG. 4 and Table 4.
TABLE 4 PXRD peaks for milrinone-fumaric acid crystals
Example 3 milrinone-maleic acid crystals
Preparation example 1
Milrinone (211 mg) and maleic acid (116 mg) are dissolved in a mixed solvent of methanol (10 mL) and trifluoroethanol (10 mL), heated and stirred in a water bath at 60 ℃ until the milrinone and the maleic acid are completely dissolved, filtered, stood at 10 ℃ for volatilization and crystallization for 24 hours, filtered and dried at 50 ℃ for 12 hours to obtain milrinone-maleic acid crystals, and the yield is: 94.5%, purity: 99.92%.
Preparation example 2
Milrinone (211 mg) and maleic acid (121 mg) are dissolved in a mixed solvent of methanol (15 mL) and acetone (15 mL), heated and stirred in a water bath at 55 ℃ until the mixture is completely dissolved, filtered, and subjected to standing, volatilizing and crystallization at 15 ℃ for 16 hours, filtered and dried at 50 ℃ for 10 hours to obtain milrinone-maleic acid crystals, and the yield is: 94.9%, purity: 99.91%.
Preparation example 3
Milrinone (106 mg) and maleic acid (58 mg) are dissolved in a mixed solvent of methanol (10 mL) and acetonitrile (10 mL), the mixture is heated and stirred in a water bath at 70 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood and volatilized at 25 ℃ for crystallization for 36h, the filtered mixture is dried at 50 ℃ for 12h to obtain milrinone-maleic acid crystals, and the yield is: 89.6%, purity: 99.91%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
Testing and resolving the crystallographic data (as Table 5) of the crystalline form of milrinone-maleic acid prepared according to the invention are monoclinic crystal system, the space group being P2 1 And/c, the unit cell parameters are as follows: α=90 °, β= 99.0870 (10) °, γ=90°, unit cell volume +.>
TABLE 5 Milrinon-maleic acid Crystal principal crystallographic data
The ORTEP diagram of the milrinone-maleic acid crystals of the present invention shows that one molecule of milrinone binds one molecule of maleic acid in this crystalline form, as shown in fig. 8. The hydrogen bond diagram of milrinone-maleic acid crystals of the present invention is shown in figure 9. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray diffraction pattern (Cu-K alpha) are shown in FIG. 7 and Table 6.
TABLE 6 PXRD peaks for milrinone-maleic acid crystals
Example 4 milrinone-oxalic acid crystals
Preparation example 1
Milrinone (316 mg) and oxalic acid (135 mg) are dissolved in a mixed solvent of methanol (15 mL) and trifluoroethanol (15 mL), the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood and volatilized at 10 ℃ for crystallization for 24 hours, the filtered mixture is dried at 60 ℃ for 10 hours to obtain milrinone-oxalic acid crystals, and the yield is: 95.1 percent of purity: 99.89%.
Preparation example 2
Milrinone (316 mg) and oxalic acid (142 mg) are dissolved in a mixed solvent of methanol (20 mL) and acetone (20 mL), the mixture is heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, the mixture is filtered, the mixture is stood at 15 ℃ for volatilization and crystallization for 24 hours, the mixture is filtered, and the mixture is dried at 60 ℃ for 10 hours to obtain milrinone-oxalic acid crystals, and the yield is: 94.6%, purity: 99.90%.
Preparation example 3
Milrinone (316 mg) and oxalic acid (135 mg) are dissolved in a mixed solvent of methanol (20 mL) and water (10 mL), heated in a water bath at 70 ℃ and stirred until the milrinone and oxalic acid are completely dissolved, filtered, kept stand at 20 ℃ for volatilization and crystallization for 48h, filtered and dried at 60 ℃ for 12h to obtain milrinone-oxalic acid crystals, and the yield is: 87.5%, purity: 99.89%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
Testing and resolving the crystallographic data of the crystalline form of milrinone-oxalic acid prepared according to the invention (as in Table 7) are MonocLinic crystal system with space group P2 1 And/n, the unit cell parameters are: α=90 °, β= 90.7445 (12) °, γ=90°, unit cell volume +.>
TABLE 7 Milrinon-oxalic acid Crystal principal crystallographic data
The ORTEP diagram of the milrinone-oxalic acid crystals of the present invention shows that one molecule of milrinone binds one molecule of oxalic acid in the crystalline form, as shown in fig. 11. The hydrogen bond diagram of the milrinone-oxalic acid crystal is shown in figure 12. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray diffraction pattern (Cu-K alpha) are shown in FIG. 10 and Table 8.
TABLE 8 PXRD peaks for milrinone-oxalic acid crystals
Example 5 milrinone-4-hydroxycinnamic acid crystals
Preparation example 1
Milrinone (213 mg) and 4-hydroxy cinnamic acid (164 mg) are added into a mixed solvent of methanol (15 mL) and trifluoroethanol (15 mL), heated and stirred in a water bath at 50 ℃ until the mixture is completely dissolved, filtered, stood and volatilized at 20 ℃ for crystallization for 36h, filtered and dried at 60 ℃ for 12h to obtain milrinone-4-hydroxy cinnamic acid crystals, and the yield is: 94.3%, purity: 99.94%.
Preparation example 2
Milrinone (212 mg) and 4-hydroxy cinnamic acid (163 mg) are added into a mixed solvent of ethanol (20 mL) and trifluoroethanol (20 mL), heated and stirred in a water bath at 50 ℃ until the mixture is completely dissolved, filtered, stood at 25 ℃ for volatilization and crystallization for 36h, filtered and dried at 60 ℃ for 12h to obtain milrinone-4-hydroxy cinnamic acid crystals, and the yield is: 92.6%, purity: 99.93%.
Preparation example 3
Milrinone (212 mg) and 4-hydroxy cinnamic acid (165 mg) are added into a mixed solvent of methanol (10 mL) and trifluoroethanol (10 mL), heated and stirred in a water bath at 40 ℃ until the mixture is completely dissolved, filtered, stood at 25 ℃ for volatilization and crystallization for 48 hours, filtered and dried at 60 ℃ for 12 hours, thus obtaining milrinone-4-hydroxy cinnamic acid crystals with the yield: 89.1%, purity: 99.87%.
Preparation example 4
Milrinone (212 mg) and 4-hydroxy cinnamic acid (200 mg) are added into a mixed solvent of acetonitrile (25 mL) and acetone (25 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, stood at 30 ℃ for volatilization and crystallization for 72h, filtered and dried at 60 ℃ for 12h to obtain milrinone-4-hydroxy cinnamic acid crystals, and the yield is: 86.7%, purity: 99.75%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
Testing and analysis of the crystallographic data (as in Table 9) of the crystalline form of the milrinone-4-hydroxycinnamic acid co-crystal prepared according to the invention are triclinic, the space group P-1, the unit cell parameters:α= 93.9650 (10) °, β= 94.6000 (10) °, γ= 109.6110 (10) °, unit cell volume +.>
TABLE 9 major crystallographic data for milrinone-4-hydroxycinnamic acid crystals
The ORTEP diagram of the milrinone-4-hydroxycinnamic acid co-crystal of the present invention shows that one molecule of milrinone binds one molecule of 4-hydroxycinnamic acid in this crystalline form, as shown in fig. 14. The hydrogen bond diagram of the milrinone-4-hydroxy cinnamic acid eutectic of the invention is shown in figure 15. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray diffraction pattern (Cu-K alpha) are shown in FIG. 13 and Table 10.
TABLE 10 PXRD peak of milrinone-4-hydroxycinnamic acid crystals
Example 6 milrinone-1-hydroxy-2-naphthoic acid crystals
Preparation example 1
Milrinone (316.5 mg) and 1-hydroxy-2-naphthoic acid (282.3 mg) are dissolved in a mixed solvent of methanol (15 mL) and trifluoroethanol (15 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, and subjected to standing, volatilizing and crystallizing for 24 hours at 15 ℃, filtered and dried for 12 hours at 50 ℃ to obtain milrinone-1-hydroxy-2-naphthoic acid crystals, and the yield is: 96.2%, purity: 99.91%.
Preparation example 2
Milrinone (211.1 mg) and 1-hydroxy-2-naphthoic acid (197.6 mg) are dissolved in a mixed solvent of methanol (15 mL) and acetone (15 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, stood at 10 ℃ for volatilization and crystallization for 36h, filtered and dried at 50 ℃ for 12h to obtain milrinone-1-hydroxy-2-naphthoic acid crystals, and the yield is: 95.8%, purity: 99.92%.
Preparation example 3
Milrinone (316.5 mg) and 1-hydroxy-2-naphthoic acid (282.3 mg) are dissolved in a mixed solvent of methanol (20 mL) and trifluoroethanol (20 mL), heated and stirred in a water bath at 50 ℃ until the mixture is completely dissolved, filtered, and subjected to standing, volatilizing and crystallizing for 36h at 25 ℃, filtered and dried for 12h at 50 ℃ to obtain milrinone-1-hydroxy-2-naphthoic acid crystals, and the yield is: 91.2%, purity: 99.91%.
Preparation example 4
Milrinone (211 mg) and 1-hydroxy-2-naphthoic acid (226 mg) are dissolved in a mixed solvent of methanol (25 mL) and trifluoroethanol (20 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, and subjected to standing, volatilizing and crystallization at 15 ℃ for 36h, filtered and dried at 50 ℃ for 12h to obtain milrinone-1-hydroxy-2-naphthoic acid crystals, and the yield is: 90.5%, purity: 99.89%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
Testing and analysis of the crystallographic data (see Table 11) for the crystalline form of milrinone-1-hydroxy-2-naphthoic acid prepared according to the invention are that the triclinic crystal system has a space group of P-1 and the unit cell parameters are:α= 70.444 (10) °, β= 86.165 (9) °, γ= 72.457 (9) °, unit cell volume +.>
TABLE 11 data on major crystallography of milrinone-1-hydroxy-2-naphthoic acid crystals
The ORTEP diagram of the milrinone-1-hydroxy-2-naphthoic acid crystal of the present invention shows that one molecule of milrinone binds one molecule of 1-hydroxy-2-naphthoic acid in the crystalline form, as shown in FIG. 17. The hydrogen bond diagram of milrinone-1-hydroxy-2-naphthoic acid is shown in figure 18. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray diffraction pattern (Cu-K alpha) are shown in FIG. 16 and Table 12.
TABLE 12 PXRD peaks for milrinone-1-hydroxy-2-naphthoic acid crystals
Example 7 milrinone-2-indolecarboxylic acid crystals
Preparation example 1
Milrinone (211.1 mg) and 2-indolecarboxylic acid (163.5 mg) are added into a mixed solvent of ethanol (10 mL) and acetone (8 mL), the mixture is heated and stirred in a water bath at 68 ℃ until the mixture is completely dissolved, the mixture is filtered, and the mixture is left to stand, volatilize and crystallize at 15 ℃ for 48 hours, filtered and dried at 50 ℃ for 12 hours, thus obtaining milrinone-2-indolecarboxylic acid crystals with the yield: 97.3%, purity: 99.91%.
Preparation example 2
Milrinone (211.1 mg) and 2-indolecarboxylic acid (161.5 mg) are added into a mixed solvent of ethanol (20 mL), trifluoroethanol (20 mL) and acetone (9 mL), heated and stirred in a water bath at 65 ℃ until the mixture is completely dissolved, filtered, and subjected to standing, volatilizing and crystallization at 15 ℃ for 48h, filtered and dried at 50 ℃ for 12h to obtain milrinone-2-indolecarboxylic acid crystals, and the yield is: 95.7%, purity: 99.93%.
Preparation example 3
Milrinone (211.1 mg) and 2-indolecarboxylic acid (163.5 mg) are added into a mixed solvent of ethanol (15 mL) and acetonitrile (15 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, stood at 10 ℃ for volatilization and crystallization for 48 hours, filtered and dried at 50 ℃ for 12 hours to obtain milrinone-2-indolecarboxylic acid crystals with the yield: 90.6%, purity: 99.88%.
Preparation example 4
Milrinone (211 mg) and 2-indolecarboxylic acid (193 mg) are added into a mixed solvent of ethanol (30 mL) and methanol (30 mL), heated and stirred in a water bath at 68 ℃ until the mixture is completely dissolved, filtered, stood at 20 ℃ for volatilization and crystallization for 72h, filtered and dried at 60 ℃ for 12h to obtain milrinone-2-indolecarboxylic acid crystals, and the yield is: 87.3%, purity: 99.89%.
Confirmation of Crystal Structure
In the drug crystal test of milrinone, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
Testing and analyzing the crystallographic data (as in Table 13) of the crystalline form of milrinone-2-indolecarboxylic acid prepared by the invention, the crystallographic parameters are: monoclinic crystal system with space group P2 1 And/c, the unit cell parameters are as follows: α=90 °, β= 98.093 (2) °, γ=90°, unit cell volume +.>
TABLE 13 major crystallographic data for milrinone-2-indolecarboxylic acid crystals
The ORTEP diagram of the milrinone-2-indolecarboxylic acid crystals of the present invention shows that one molecule of milrinone binds one molecule of 2-indolecarboxylic acid in the crystalline form, as shown in fig. 20. The hydrogen bond diagram of the milrinone-2-indolecarboxylic acid crystal is shown in figure 21. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray diffraction pattern (Cu-K alpha) are shown in FIG. 19 and Table 14.
Table 14 PXRD peaks for milrinone-2-indolecarboxylic acid crystals
Stability test
The milrinone crystals used in the experiments were prepared with reference to patent CN106361710 a.
The specific stability test method is carried out by referring to the guidance method of the fourth section of the Chinese pharmacopoeia on stability investigation.
High temperature test: placing the sample in a clean container, standing at 60deg.C for 10 days, sampling at 5 th and 10 th days, and detecting purity by HPLC;
high humidity test: placing the sample in a constant humidity closed container at 25 ℃ under the conditions of 90% and 5% relative humidity for 10 days, sampling on the 5 th day and the 10 th day, and detecting the purity by using an HPLC method;
strong light irradiation test: the sample was placed in an illumination device equipped with a fluorescent lamp, and left for 10 days under the condition of an illuminance of 4500lx and 500lx, and samples were taken on days 5 and 10, and the purity was measured by HPLC.
TABLE 15 stability test results of crystals
Solubility test
The method comprises the following steps: respectively weighing 10ml of medium (water, 0.01mol/LHCl solution) in a penicillin bottle, adding excessive sample to be tested, sealing the penicillin bottle, placing in a constant-temperature water bath at 25 ℃ for stirring for 1 hour, filtering by a filter membrane, and taking filtrate; HPLC detection and calculation of the concentration of saturated solution according to external standard method. Milrinone crystals are hardly dissolved.
Table 16 solubility of crystals in various media (mg/mL)

Claims (10)

1. A pharmaceutical polymorph of milrinone, characterized in that the pharmaceutical polymorph comprises milrinone and a compound comprising carboxylic acid groups in its crystal structure; the crystal is specifically selected from milrinone-malonic acid crystal, milrinone-fumaric acid crystal, milrinone-maleic acid crystal, milrinone-oxalic acid crystal, milrinone-4-hydroxy cinnamic acid crystal, milrinone-1-hydroxy-2-naphthoic acid crystal and milrinone-2-indolecarboxylic acid crystal.
2. The pharmaceutical polymorph of claim 1, wherein said milrinone-malonic acid crystals have characteristic peaks in the X-ray diffraction pattern expressed in terms of 2Θ at least at 10.3 ± 0.2 °, 15.3 ± 0.2 °, 24.3 ± 0.2 ° using Cu-ka radiation.
3. The pharmaceutical polymorph of claim 1, wherein said milrinone-fumaric acid crystals have X-ray diffraction patterns, expressed as 2Θ, having characteristic peaks at least at 15.6 ± 0.2 °, 18.3 ± 0.2 °, 23.7 ± 0.2 °, 26.1 ± 0.2 °, 26.2 ± 0.2 °, 29.6 ± 0.2 °.
4. The pharmaceutical polymorph of claim 1, wherein said milrinone-maleic acid crystals are characterized by X-ray diffraction patterns expressed in terms of 2Θ using Cu-ka radiation at least at 17.1 ± 0.2 °, 19.0 ± 0.2 °, 20.0 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 25.2 ± 0.2 °, 27.8 ± 0.2 °.
5. The pharmaceutical polymorph of claim 1, wherein said milrinone-oxalic acid crystals have characteristic peaks in the X-ray diffraction pattern expressed in 2Θ at least at 14.5 ± 0.2 °, 18.5 ± 0.2 °, 23.2 ± 0.2 °, 28.8 ± 0.2 °, 36.8 ± 0.2 ° using Cu-ka radiation.
6. The pharmaceutical polymorph of claim 1, wherein said milrinone-4 hydroxycinnamic acid crystals have characteristic peaks expressed in 2Θ in X-ray diffraction patterns at least at 5.9 ± 0.2 °, 14.7 ± 0.2 °, 19.0 ± 0.2 °, 25.0 ± 0.2 °, 25.2 ± 0.2 °, 30.8 ± 0.2 ° using Cu-ka radiation.
7. The pharmaceutical polymorph of claim 1, wherein said milrinone-1-hydroxy-2-naphthoic acid crystals have characteristic peaks in X-ray diffraction patterns expressed in 2Θ of at least 12.9 ± 0.2 °, 24.4 ± 0.2 °, 25.0 ± 0.2 °, 25.1 ± 0.2 ° using Cu-ka radiation.
8. The pharmaceutical polymorph of claim 1, wherein said milrinone-2-indolecarboxylic acid crystals are characterized by an X-ray diffraction pattern expressed as 2Θ using Cu-ka radiation having peaks at least at 7.9 ± 0.2 °, 12.5 ± 0.2 °, 16.7 ± 0.2 °, 19.2 ± 0.2 °, 22.9 ± 0.2 °, 25.4 ± 0.2 °, 26.5 ± 0.2 °.
9. A method of preparing the pharmaceutical polymorph of claim 1, comprising the steps of: dissolving milrinone and a compound containing carboxylic acid in a mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain a medicine crystal; wherein the carboxylic acid-containing compound is selected from malonic acid, fumaric acid, maleic acid, oxalic acid, 4-hydroxycinnamic acid, 1-hydroxy-2-naphthoic acid or 2-indolecarboxylic acid.
10. Use of a pharmaceutical polymorph of milrinone according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of a disease comprising heart failure.
CN202210280420.4A 2022-03-21 2022-03-21 Pharmaceutical polycrystals of milrinone Pending CN116813542A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210280420.4A CN116813542A (en) 2022-03-21 2022-03-21 Pharmaceutical polycrystals of milrinone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210280420.4A CN116813542A (en) 2022-03-21 2022-03-21 Pharmaceutical polycrystals of milrinone

Publications (1)

Publication Number Publication Date
CN116813542A true CN116813542A (en) 2023-09-29

Family

ID=88117140

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210280420.4A Pending CN116813542A (en) 2022-03-21 2022-03-21 Pharmaceutical polycrystals of milrinone

Country Status (1)

Country Link
CN (1) CN116813542A (en)

Similar Documents

Publication Publication Date Title
US20090076272A1 (en) Polymorphs of eszopiclone malate
CN112142679A (en) Gefitinib and vanillic acid eutectic methanol solvate and preparation method thereof
JP2023509242A (en) Co-crystals of novel empagliflozin
RU2719484C2 (en) Sodium salt of the uric acid transporter inhibitor and its crystalline form
CN116813542A (en) Pharmaceutical polycrystals of milrinone
CN112110865B (en) Isonicotinamide acipimox cocrystal II and preparation method thereof
CN111518040B (en) Methylpyrazine derivative-piperazine eutectic
CN116813541A (en) Co-crystal for milriness pesticide and preparation method thereof
CN113754596A (en) Gefitinib co-crystal
CN117105857A (en) Milrinone-cinnamic acid crystal and preparation method thereof
CN117105855A (en) Milrinone-saccharin crystal form
CN116239525A (en) Milrinone-baicalein co-crystal
CN107043405B (en) Crystal form of polycyclic heterocyclic compound, preparation method, application and composition thereof
CN116410131A (en) Mili pesticide co-crystal and preparation method thereof
CN117069653A (en) Milrinone gallic acid eutectic
CN117105856A (en) Milrinone-sulfamic acid crystal and preparation method thereof
CN114181211B (en) Ketorolac and benzamide eutectic and preparation method thereof
CN117105858A (en) Milrinone-3, 5-pyridine dicarboxylic acid hydrate crystal form
CN117105854A (en) Milrinone-nicotinic acid crystal and preparation method thereof
CN113929630B (en) Gefitinib drug co-crystal
CN116813543A (en) Milrinone eutectic solvate
CN116253680A (en) Milrinone and ketorolac eutectic crystal and preparation method thereof
CN114656448A (en) Topiroxostat-sulfamic acid eutectic crystal
KR102150825B1 (en) Novel sglt-2 inhibitors cocrystal
CN116239522A (en) Milrinone-succinic acid co-crystal

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination